Comparison of Clinical Subtypes of Breast Cancer within the Claudin-Low Molecular Cluster Reveals Distinct Phenotypes

Voutsadakis, Ioannis A.

doi:10.3390/cancers15102689

Cited by 9 publications

(10 citation statements)

References 49 publications

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“…The former have higher proliferation potential and the latter possess motility capabilities favoring movement and tissue infiltration. Previous works have established that, although claudin-low cancers are mostly triple-negative, a smaller sub-set of them can be ER-positive and/or HER2-positive [9,10,28]. Among all cancers with the claudin-low phenotype in the METABRIC cohort, 68.4% are ER-negative/HER2-negative, but 25.3% and 6.3% are ER-positive/HER2-negative and HER2-positive, respectively [9,10].…”

Section: Discussionmentioning

confidence: 97%

“…Previous works have established that, although claudin-low cancers are mostly triple-negative, a smaller sub-set of them can be ER-positive and/or HER2-positive [9,10,28]. Among all cancers with the claudin-low phenotype in the METABRIC cohort, 68.4% are ER-negative/HER2-negative, but 25.3% and 6.3% are ER-positive/HER2-negative and HER2-positive, respectively [9,10]. The EMT core regulators ZEB1, ZEB2, Snail, Slug and TWIST1 are up-regulated in claudin-low cancers independently of the status of ER expression.…”

Section: Discussionmentioning

confidence: 99%

“…The claudin-low group of breast cancers presents, as a defining characteristic, the down-regulation of the expression of adhesion proteins such as claudins 3, 4 and 7, occludin and E cadherin. These cancers are mostly, but not exclusively, triple-negative by immunohistochemistry [9,10]. The down-regulation of adhesion molecules results in the loss of epithelial cell adhesions and the up-regulation of mesenchymal proteins such as vimentin and N cadherin [11].…”

Section: Introductionmentioning

confidence: 99%

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EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

Voutsadakis

2023

CIMB

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Background: Breast cancers are heterogeneous and are classified according to the expression of ER, PR and HER2 receptors to distinct groups with prognostic and therapeutic implications. Within the triple-negative group, with no expression of these three receptors, molecular heterogeneity exists but is currently not exploited in the clinic. The claudin-low phenotype is present in a subset of triple-negative breast cancers and constitutes together with basal-like cancers the most extensive groups within triple-negative breast cancers. Suppression of epithelial cell adhesion molecules in claudin-low cancers is also a hallmark of Epithelial Mesenchymal Transition (EMT). Methods: The groups of claudin-low and claudin-non-suppressed breast cancers from the extensive publicly available genomic cohorts of the METABRIC study were examined to delineate and compare their molecular landscape. Genetic and epigenetic alterations of key factors involved in EMT and potentially associated with the pathogenesis of the claudin-low phenotype were analyzed in the two groups. Results: Claudin-low cancers displayed up-regulation of several core transcription factors of EMT at the mRNA level, compared with claudin-non-suppressed breast cancers. Global promoter DNA methylation was increased in both groups of triple-negative cancers and in claudin-low ER-positive cancers compared with the rest of ER-positive cancers. Histone modifier enzymes, including methyltransferases, demethylases, acetyltransferases and deacetylases displayed amplifications more frequently in claudin-non-suppressed triple-negative cancers than in claudin-low counterparts and the expression of some of these enzymes differed significantly between the two groups. Conclusion: Claudin-low and claudin-non-suppressed triple-negative breast cancers differ in their landscape of EMT core regulators and epigenetic regulators. These differences may be explored as targets for therapeutic interventions specific to the two groups of triple-negative breast cancers.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

Voutsadakis

2023

CIMB

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“…Claudins present infrequent genetic lesions, such as mutations or copy number alterations in cancers. Instead, tight junction upregulation or downregulation relies on transcriptional and post-transcriptional regulations [30]. In addition, the process of EMT in cancer allows the creation of intermediate cell states that have undergone only partial mesenchymal transformation, thus retaining some epithelial characteristics.…”

Section: Discussionmentioning

confidence: 99%

Tight Junction Claudins and Occludin Are Differentially Regulated and Expressed in Genomically Defined Subsets of Colon Cancer

Voutsadakis

2023

CIMB

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Metastatic colon cancer remains incurable despite improvements in survival outcomes. New therapies based on the discovery of colon cancer genomic subsets could improve outcomes. Colon cancers from genomic studies with publicly available data were examined to define the expression and regulation of the major tight junction proteins claudins and occludin in genomic groups. Putative regulations of the promoters of tight junction genes by colon-cancer-deregulated pathways were evaluated in silico. The effect of claudin mRNA expression levels on survival of colon cancer patients was examined. Common mutations in colon-cancer-related genes showed variable prevalence in genomically identified groups. Claudin genes were rarely mutated in colon cancer patients. Genomically identified groups of colon cancer displayed distinct regulation of claudins and occludin at the mRNA level. Claudin gene promoters possessed clustered sites of binding sequences for transcription factors TCF4 and SMADs, consistent with a key regulatory role of the WNT and TGFβ pathways in their expression. Although an effect of claudin mRNA expression on survival of colon cancer patients as a whole was not prominent, survival of genomic subsets was significantly influenced by claudin mRNA expression. mRNA expression of the main tight junction genes showed differential regulation in various genomically defined subgroups of colon cancer. These data pinpoint a distinct role of claudins and pathways that regulate them in these subgroups and suggest that subgroups of colon cancer should be considered in future efforts to therapeutically target claudins.

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“…This may be along with the down-regulation of E-cadherin and other molecular changes, CLBC is more prone to ductal carcinoma. Characteristically, in contrast to lobular carcinoma, downregulation of E-cadherin in CLBC is associated with epigenetic or posttranscriptional dysregulation ( 121 ).…”

Section: Clinicopathological Characteristics Of Claudin-low Breast Ca...mentioning

confidence: 99%

Research progress of Claudin-low breast cancer

Pan,

Xu,

et al. 2023

Front. Oncol.

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Claudin-low breast cancer (CLBC) is a subgroup of breast cancer discovered at the molecular level in 2007. Claudin is one of the primary proteins that make up tight junctions, and it plays crucial roles in anti-inflammatory and antitumor responses as well as the maintenance of water and electrolyte balance. Decreased expression of claudin results in the disruption of tight junction structures and the activation of downstream signaling pathways, which can lead to tumor formation. The origin of Claudin-low breast cancer is still in dispute. Claudin-low breast cancer is characterized by low expression of Claudin3, 4, 7, E-cadherin, and HER2 and high expression of Vimentin, Snai 1/2, Twist 1/2, Zeb 1/2, and ALDH1, as well as stem cell characteristics. The clinical onset of claudin-low breast cancer is at menopause age, and its histological grade is higher. This subtype of breast cancer is more likely to spread to lymph nodes than other subtypes. Claudin-low breast cancer is frequently accompanied by increased invasiveness and a poor prognosis. According to a clinical retrospective analysis, claudin-low breast cancer can achieve low pathological complete remission. At present, although several therapeutic targets of claudin-low breast cancer have been identified, the effective treatment remains in basic research stages, and no animal studies or clinical trials have been designed. The origin, molecular biological characteristics, pathological characteristics, treatment, and prognosis of CLBC are extensively discussed in this article. This will contribute to a comprehensive understanding of CLBC and serve as the foundation for the individualization of breast cancer treatment.

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Comparison of Clinical Subtypes of Breast Cancer within the Claudin-Low Molecular Cluster Reveals Distinct Phenotypes

Cited by 9 publications

References 49 publications

EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

Tight Junction Claudins and Occludin Are Differentially Regulated and Expressed in Genomically Defined Subsets of Colon Cancer

Research progress of Claudin-low breast cancer

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